Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 83300024, Santiago, CP, Chile.
Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
BMC Genomics. 2018 Oct 5;19(1):731. doi: 10.1186/s12864-018-5110-2.
The high-density lipoprotein receptor SR-B1 mediates cellular uptake of several lipid species, including cholesterol and vitamin E. During early mouse development, SR-B1 is located in the maternal-fetal interface, where it facilitates vitamin E transport towards the embryo. Consequently, mouse embryos lacking SR-B1 are vitamin E-deficient, and around half of them fail to close the neural tube and show cephalic neural tube defects (NTD). Here, we used transcriptomic profiling to identify the molecular determinants of this phenotypic difference between SR-B1 deficient embryos with normal morphology or with NTD.
We used RNA-Seq to compare the transcriptomic profile of three groups of embryos retrieved from SR-B1 heterozygous intercrosses: wild-type E9.5 embryos (WT), embryos lacking SR-B1 that are morphologically normal, without NTD (KO-N) and SR-B1 deficient embryos with this defect (KO-NTD). We identified over 1000 differentially expressed genes: down-regulated genes in KO-NTD embryos were enriched for functions associated to neural development, while up-regulated genes in KO-NTD embryos were enriched for functions related to lipid metabolism. Feeding pregnant dams a vitamin E-enriched diet, which prevents NTD in SR-B1 KO embryos, resulted in mRNA levels for those differentially expressed genes that were more similar to KO-N than to KO-NTD embryos. We used gene regulatory network analysis to identify putative transcriptional regulators driving the different embryonic expression profiles, and identified a regulatory circuit controlled by the androgen receptor that may contribute to this dichotomous expression profile in SR-B1 embryos. Supporting this possibility, the expression level of the androgen receptor correlated strongly with the expression of several genes involved in neural development and lipid metabolism.
Our analysis shows that normal and defective embryos lacking SR-B1 have divergent expression profiles, explained by a defined set of transcription factors that may explain their divergent phenotype. We propose that distinct expression profiles may be relevant during early development to support embryonic nutrition and neural tube closure.
高密度脂蛋白受体 SR-B1 介导包括胆固醇和维生素 E 在内的几种脂质的细胞摄取。在早期的小鼠发育过程中，SR-B1 位于母体-胎儿界面，在那里它促进维生素 E 向胚胎的转运。因此，缺乏 SR-B1 的小鼠胚胎缺乏维生素 E，其中大约一半的胚胎无法关闭神经管，表现出头颅神经管缺陷 (NTD)。在这里，我们使用转录组谱分析来鉴定缺乏 SR-B1 的胚胎具有正常形态或具有 NTD 之间表型差异的分子决定因素。
我们使用 RNA-Seq 比较了从 SR-B1 杂合子相互交配中回收的三组胚胎的转录组谱：野生型 E9.5 胚胎 (WT)、形态正常、无 NTD 的缺乏 SR-B1 的胚胎 (KO-N) 和缺乏 SR-B1 且存在此缺陷的胚胎 (KO-NTD)。我们鉴定了 1000 多个差异表达基因：KO-NTD 胚胎中下调的基因富集了与神经发育相关的功能，而 KO-NTD 胚胎中上调的基因富集了与脂质代谢相关的功能。用富含维生素 E 的饮食喂养怀孕的母鼠，可预防 SR-B1 KO 胚胎的 NTD，导致那些差异表达基因的 mRNA 水平更类似于 KO-N 而不是 KO-NTD 胚胎。我们使用基因调控网络分析来鉴定可能驱动不同胚胎表达谱的潜在转录因子，并鉴定了一个由雄激素受体控制的调节回路，该回路可能导致 SR-B1 胚胎中这种二分表达谱。支持这种可能性，雄激素受体的表达水平与几个参与神经发育和脂质代谢的基因的表达密切相关。
我们的分析表明，缺乏 SR-B1 的正常和有缺陷的胚胎具有不同的表达谱，这可以用一组特定的转录因子来解释，这些转录因子可能解释了它们不同的表型。我们提出，不同的表达谱在早期发育中可能与胚胎营养和神经管闭合有关。
